Dyslipidemia, including excess production and secretion of triglycerides and cholesterol by the liver, is a prominent metabolic abnormality of type 2 diabetes that can lead to the development of atherosclerosis and coronary artery disease. The relative roles of insulin resistance and hyperglycemia in the pathophysiology of this process are unclear, as are the cellular events that lead to dyslipidemia. Recently it has come to light that the transcription factor FoxO1 is an important effector in the pathway linking insulin signaling to lipoprotein turnover, in addition to its established role in regulating glucose production. Because FoxO1 can be regulated by both insulin (through phosphorylation-dependent inactivation) and glucose (through deacetylation- dependent activation), we reasoned that abnormalities of FoxO1 function might provide a unifying mechanism for the dyslipidemia of diabetes. To characterize FoxO1's contribution to lipoprotein metabolism, we will analyze lipid and cholesterol metabolism in liver-specific FoxO1 knockout mice (L-FoxO1) in two different conditions of metabolic stress: In Aim 1, mice will be rendered diabetic with streptozotocin (STZ), allowing us to examine the role of FoxO1 during hyperglycemia. In Aim 2, L-FoxO1 and controls will be bred onto an atherosclerosis- prone strain background (LDLR-/-) and fed a high fat, high cholesterol diet, wherein the role of FoxO1 in the development of atherosclerosis can be determined. Preliminary experiments relevant to Aim 1 demonstrated that hyperglycemic L-FoxO1 mice had high levels of serum triglycerides, cholesterol, and free fatty acids, and the rate of secretion of very low density lipoprotein from the liver was significantly increased. Investigation into the mechanism of FoxO1's effect on lipid metabolism is necessary to achieve the goals of this proposal, and will allow us to reexamine the complex relationship between insulin resistance, hyperglycemia and atherosclerosis. PUBLIC HEALTH RELEVANCE: Cardiovascular diseases remain the leading cause of death in the US population. Atherosclerosis and coronary artery disease are tightly linked to diabetes, but the connection between these diseases remains unclear. Identifying the key players in this relationship, including genetic effectors such as the FoxO1 gene, and metabolic parameters such as hyperglycemia and insulin resistance, will improve our understanding of these diseases and how to treat patients more effectively.